Synthesis Of The Novel Immunosuppressant FTY-720

The immunosuppressant is a kind of medicine which has the immunosuppression function, is a new drug which develops on the multi-disciplinary research foundation of the tumor chemotherapy, the organ transplanting, the immune pathology and the clinical immunology and so on, may suppresses organismal immunity function through the influencing organismal immune response and the immune pathological reaction, at present it has widely applied in the organ transplanting anti-repel response and the treatment of own immunity disease.Until now, the research history about immunosuppressant has become about 90 years, from 1914 had the report about sole organic compound benzene possible to cause the immunosuppression to start, the people deepened gradually to the immunity inhibitor understanding, it has become the key point and the hot spot of the medicine researching.At present the most immunosuppressant lacks the specificity, often simultaneously affects organism normal immunity reply function in the treatment. At the same time, because the immune response originally is the organism protecting it's own defense reaction, suppressing this kind of response for a long time to be able to bring the infection and the suggestion tumor and some other serious consequences, this is the question which meeting in the immunosuppressant application. The ideal immunosuppressant should be the selectivity strongly, the function fast, the effect obviously, stopping take the medicine after-effect to be reversible, side-effect few, does not damage organism normal immunity function. Therefore, seeks highly effective, the low poisonous immunosuppressant is the current pharmacy worker's urgent duty.In the 1994 Fujita et al discovered a unique immunosuppressant, ISP-1 , from the fermentation broth of Isaria sinclairii (ATCC24400), which has the obvious immunosuppression function .Take it as the forerunner compound, carries on the construction effect relations to it the research and the structure transformation,The discovery with the hydroxymethyl replace member in carboxyl group, causes it to transform as the chiral compound, still had the obvious immunosuppression activeness,Further carries on the structure optimization to discover 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY-720) function activeness is strongest.Although people had not expounded to the FTY-720 immunosuppression action mechanism, but its unique function mechanism already demonstrated the stronger immunosuppression activeness and a lower toxicity. Main characteristic:1) Remarkable immunosuppression function: Not only may preventing the acute repel occurrence, but also may reversing the repel response which already occurred; 2) With other immunosuppressant synergism: At present studies indicated FTY-720 and CsA, FK506 and Rapa the element has the synergism, Moreover the FTY-720/CsA/Rapa three association therapy synergism is stronger; 3) Unique pharmacological action: With CsA and FK506 and so on the completely different pharmacological action;4) The side effect is low, FTY720 ,The use dosage scope is very broad, Also does not have some other immunosuppressant common renal toxicity .Precisely because of these merits FTY-720 will become the novel immunosuppressant hopefully. The literature report FTY-720 synthetic method is take the phenethyl acetate as material, After the Friedel-Crafts Reaction with the octanoyl chloride et al, the process of synthesis total 8 steps obtains FTY-720. The total recovery only has about 4%. Another literature to enhance in addition the production rate to 13% about, but uses outset raw material phenyloctane is limited in the domestic originWe design the FTY-720 process of synthesis is the benzene which easy to result in by the economy for the material,In under the anhydrous AlCl3 catalysis, After the Friedel-Crafts Reaction with the octanoyl chloride obtains the compound (1),using the CF3COOH and Et3SiH to transform the ketone into methylene obtains the compound (2), Friedel-Crafts acylation of the compound (2) with the bromoacetyl bromide using AlCl3 obtains the compound (4),using the TiCl4 and Et3SiH to transform the ketone into methylene obtains the compound (5), Finally obtains end product FTY-720, After improvement process of synthesis total 9 steps, total recovery 17% The structure of the target molecule and the key intermediates was confirmed by IR, 1H NMR, 13C NMR, MS.This paper described the synthetic method of FTY-720 through the reasonable process of synthesis, caused the origin of material drug to be more convenient, reduces the production cost, the operation has been simple, more suitable industrialization production.